Emerging knowledge of the contribution of the serotonergic neurobiology of addiction can be utilized to design new pharmacotherapies based upon serotonergic mechanisms. Preclinical findings strongly suggest that a 5-HT2AR antagonist, a 5-HT2cR agonist or ligands with a combination of these actions might be a useful approach to reduce craving and enhance abstinence in addiction. The goal of Project 3 of the Translational Center for Serotonin and Stimulant Addiction (TCSSA) is to utilize medicinal chemistry methodology to create a series of bivalent homodimers of two 5-HT2AR antagonist molecules or two 5-HT2cR agonist molecules with the promise of increased selectivity for these receptors, as well as a series of bivalent heterodimers containing a selective 5-HTaAR antagonist molecule and a 5-HT2CR agonist molecule. The dimers will be based on the highly selective 5-HT^R antagonist M100907 and 5-HT2CR agonist WAY 470. Given the limited knowledge of how 5-HT ligands interact with their respective receptors, two derivatives of each molecule will be examined. These analogs will differ based upon the point of connection of the tether to the molecule. Prior to synthesizing dimers linked at these locations, the corresponding monomer controls possessing a model for the tether will be synthesized and evaluated to determine which locations of attachment are benign. Project 3 will work closely with Core B to screen these new molecules for functional activity at wild-type 5-HT^R and 5-HT2CR, as well as at 5-HT^R and 5-HT2CR with genetic polymorphisms that characterize the cocaine-dependent population (Project 1). This discovery research will create important mechanistic understanding of the serotonergic system and its role in addiction biology (with Core B, Project 2) and bring these together with clinical insights and facilitate "proof-of-concept" in humans (Project 1). Project 3 represents a high risk/exploratory project and a translational bridge between human and animal psychopharmacology, medicinal chemistry, molecular biology and pharmacology which allows the rational design of new molecules and drives innovation at the interfaces of biology and chemistry as well as biomedical and clinical research. With the knowledge gained during this developmental period, we will build upon our new understanding of the molecular, cellular and structural biology of the 5-HT2AR and 5-HT2CR and the emerging biology of dimerization in living systems to propose additional strategies for discovery. Lav Abstract. No effective, accessible medication for the treatment of stimulant addiction is currently available. We will design and create new drugs with the promise to enhance abstinence and reduce relapse in cocaine dependence.